Enrofloxacine injection or infusion solutions

ABSTRACT

The present invention relates to novel injection and infusion solutions of the following composition: 
     a) 0.1 to 20% by weight of enrofloxacin, based on the total weight of the solution, in the form of its salts with polyhydroxycarboxylic acids or amino acids or mixtures thereof, 
     b) polyhydroxycarboxylic acids, amino acids or mixtures thereof in 0.1 to 5 molar excess, based on enrofloxacin; 
     c) optionally 0.1 to 30% by weight of formulation aids, based on the total weight of the solution; 
     d) water to 100% by weight.

This application is a 371 PCT/EP95/05147 filed Dec. 28, 1995.

The present invention relates to novel injection or infusion solutionsof enrofloxacin.

Solutions of quinolonecarboxylic acids for parenteral administration arealready known from EP-OS (European Published Specification) 67 666. Theyare based on salts of the corresponding quinolonecarboxylic acids withvarious hydroxycarboxylic acids.

Injection or infusion solutions of quinolonecarboxylic acids, inter aliaof ciprofloxacin, based on the lactic acid salts with an excess of acid,are known from EP-OS (European Published Specification) 138 018.

Aqueous infusion solutions of ca 0.01 to 0.5% of ciprofloxacin, to whichacids are added for stabilization, are known from EP-OS (EuropeanPublished Specification) 214 784. Lactic acid, in particular, ismentioned as the preferred acid in said document.

Injection solutions based on fine suspensions of quinolonecarboxylicacids are known from DE-OS (German Published Specification) 39 02 079.

The present invention relates to novel injection and infusion solutionsof the following composition:

a) 0.1 to 20% by weight of enrofloxacin, based on the total weight ofthe solution, in the form of its salts with polyhydroxycarboxylic acidsor amino acids or mixtures thereof;

b) polyhydroxycarboxylic acids, amino acids or mixtures thereof in 0.1to 5 molar excess, based on enrofloxacin;

c) optionally 0.1 to 30% by weight of formulation aids, based on thetotal weight of the solution;

d) water to 100% by weight.

Compared with the injection solutions of enrofloxacin known hitherto,the solutions according to the invention have the advantage of a potenteffect which sets in rapidly. This is shown by the fact that high bloodlevels of the active substance are reached only a short time afteradministration. However, the active substance is also eliminatedrapidly, which is a great advantage, especially in the treatment ofanimals used for food production (short waiting times).

The injection and infusion solutions according to the invention containthe active substance enrofloxacin in concentrations preferably of 1 to10%, particularly preferably of 2.5 to 10% (percent by weight based onthe total weight of the solution).

Polyhydroxycarboxylic acids which may be mentioned are gluconic acid,galacturonic acid, glucuronic acid and lactobionic acid. The acids canbe in the open-chain form or in the form of their lactones. If the acidsare used as lactones, the lactone ring is at least partially hydrolyzedbefore salt formation and complex formation with enrofloxacin takeplace. Amino acids which may be mentioned are glutamic acid and asparticacid. The polyhydroxycarboxylic acids or amino acids are present in 0.1to 5 molar excess, based on the amount of enrofloxacin in the solution.The excess of acid is preferably 0.2 to 2 molar, particularly preferably0.5 to 1 molar.

Part of the acid present in excess can also be displaced by other acids,e.g. hydrochloric acid, methanesulphonic acid, ethanesulphonic acid,propionic acid, succinic acid, glutaric acid, citric acid, ascorbicacid, phosphoric acid or lactic acid.

In addition to water for injections, the aqueous injection solutions canalso contain ethanol, glycerol, propylene glycol, polyethylene glycoland triethylene glycol, for example, as liquid vehicles. The pH can beadjusted to the range 3 to 6.5, as far as possible, by using a varietyof substances such as phosphoric acid, citric acid, Tris, ascorbic acid,acetic acid, succinic acid, tartaric acid, gluconic acid and lacticacid, and salts thereof. The pH of the aqueous formulations according tothe invention is 3 to 5.5, preferably 3.5 to 5. The osmolality of theaqueous suspensions is 200 to 900 mOsmol/kg, preferably 260 to 390mOsmol/kg, and can be adapted to isotonic conditions by the addition ofNaCl, glucose, fructose, glycerol, sorbitol, mannitol, sucrose orxylitol, or mixtures of these substances.

It is further possible to use formulation aids such as thickeners (e.g.inter alia methyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone andgelatin), absorbents, light stabilizers, crystallization retarders,complexing agents (e.g. inter alia NaEDTA, phosphates, nitrates,acetates and citrates), antioxidants (inter alia ascorbic acid, sulphitecompounds, L-cysteine, thiodipropionic acid, thiolactic acid,monothioglycerol and propyl gallate) and preservatives (inter alia PHBesters, phenol and derivatives, chlorobutanol, benzyl alcohol, ethanol,butanol, butane-1,3-diol, chlorhexidine salts, benzoic acid and salts,and sorbic acid). Local anaesthetics, for instance procainehydrochloride, lidocaine hydrochloride and the like, can optionally beadded to the solutions according to the invention.

The injection or infusion solutions according to the invention can beprepared starting from the enrofloxacin salt with the corresponding acidor from a hydrate thereof.

It is also possible, however, to prepare the salts directly in thesolution by adding the amounts of acid required for salt formation. Thedissolution can be accelerated by working at temperatures of between 30and 60° C. The solutions can be prepared under nitrogen gas.

In this way it is possible to prepare either ready-to-use solutions ofthe active substance filled into suitable containers, e.g. intoampoules, injection vials or infusion bottles, or precursors suitablefor the preparation of such solutions, e.g. concentrates or lyophilized.

The containers into which the preparations are filled can be made eitherof glass or of plastic, it being possible for the container materials toinclude substances which give the contents a particular protection, e.g.Protection from light or oxygen.

The preparation of the solutions in the following Examples can becarried out in batch vessels with or without a heat transfer jacket.When using a non-heatable vessel, preheated water can be used ifnecessary.

In general, the bulk of the solvent is introduced into the vessel andthe individual components are dissolved therein, although it is alsopossible to add the solvent to the solids.

When acids are used in the form of their lactones, they are hydrolyzedto the free acid after dissolution, generally by being heated or left tostand, before the active substance is added. The temperature used hereis 40-70° C., preferably 50-60° C.

The other constituents are subsequently dissolved in or incorporatedinto the preparation before or after cooling, with stirring. Aftermaking-up with the remainder of the solvent, the formulation can besterile-filtered through suitable bacteria-retaining filters and/orheat-sterilized.

EXAMPLES Example 1

    ______________________________________                                                        g/100 ml                                                      ______________________________________                                        Enrofloxacin 100% 10.00                                                         Gluconolactone  8.00                                                          Benzyl alcohol double dist.  1.40                                             Sodium sulphite  0.10                                                         Water for injections 86.70                                                     100 ml = 106.20 pH 3.90                                                    ______________________________________                                    

Example 2

    ______________________________________                                                      g/100 ml                                                        ______________________________________                                        Enrofloxacin 100%                                                                              5.00                                                           Gluconolactone  3.00                                                          Benzyl alcohol  1.00                                                          Water for injections 93.60                                                     100 ml = 102.60 pH 4.40                                                    ______________________________________                                    

Example 3

    ______________________________________                                                      g/100 ml                                                        ______________________________________                                        Enrofloxacin 100%                                                                              5.00                                                           Glucuronic acid  3.25                                                         Benzyl alcohol  1.00                                                          Water for injections 93.45                                                     100 ml = 102.70 pH 3.85                                                    ______________________________________                                    

Example 4

    ______________________________________                                                       g/100 ml                                                       ______________________________________                                        Enrofloxacin 100%                                                                               5.00                                                          L-Glutamic acid puriss.  2.50                                                 Benzyl alcohol  1.00                                                          Water for injections 93.80                                                     100 ml = 102.30 pH 5.15                                                    ______________________________________                                    

Example 5

    ______________________________________                                                      g/100 ml                                                        ______________________________________                                        Enrofloxacin 100%                                                                              5.00                                                           Tartaric acid  1.25                                                           Benzyl alcohol  1.00                                                          Water for injections 94.55                                                     100 ml = 101.80 pH 4.40                                                    ______________________________________                                    

Example 6

    ______________________________________                                                      g/100 ml                                                        ______________________________________                                        Enrofloxacin 100%                                                                             10.000                                                          Gluconolactone 4.000                                                          Acetic acid 100% 1.175                                                        Benzyl alcohol 1.400                                                          Sodium sulphite 0.100                                                         Water for injections 8.025                                                     100 ml = 104.700 pH 4.42                                                   ______________________________________                                    

Example 7

    ______________________________________                                                      g/100 ml                                                        ______________________________________                                        Enrofloxacin 100%                                                                             10.000                                                          Gluconolactone  4.000                                                         Glutamic acid  2.670                                                          Benzyl alcohol  1.400                                                         Sodium sulphite  0.100                                                        Water for injections 87.330                                                    100 ml = 105.500 pH 4.28                                                   ______________________________________                                    

We claim:
 1. An injectible or infusible solution comprising a saltformed from:a) 0.1 to 20% by weight of enrofloxacin; and b) 0.1 to 5molar excess, based on enrofloxacin, of gluconic acid, glucuronic acid,glutamic acid, tartaric acid or a mixture thereof;and additionallycomprising: c) optionally 0.1 to 30% by weight of one or moreformulation aids; and d) to 100% by weight of water; all amounts byweight being based on the total weight of the solution.
 2. Theinjectible or infusible solution according to claim 1, wherein theamount of enrofloxacin is from 2.5 to 10% by weight of the solution. 3.A process for the preparation of an injectible or infusible solutionaccording to claim 1 comprising stirring the enrofloxacin into anaqueous solution of acid or mixture of acids, optionally adding theformulation aids, and optionally diluting with additional water.
 4. Amethod for combatting bacteria in an animal comprising injecting orinfusing said animal with an injectible or infusible solution accordingto claim 1.